{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:05:41Z","timestamp":1788455141790,"version":"build-2803163510"},"reference-count":30,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2018,7,23]],"date-time":"2018-07-23T00:00:00Z","timestamp":1532304000000},"content-version":"vor","delay-in-days":68,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_ccby_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["MH096463"],"award-info":[{"award-number":["MH096463"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL118561"],"award-info":[{"award-number":["HL118561"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS076517"],"award-info":[{"award-number":["NS076517"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P27746"],"award-info":[{"award-number":["P27746"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["W1232"],"award-info":[{"award-number":["W1232"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005788","name":"Medizinische Universit\u00e4t Wien","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100005788","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the \u03b1+\/\u03b32\u2013 interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into \u03b1+\/\u03b32\u2013 homology models suggested that a chiral methyl group, which is known to promote preferred binding to \u03b15-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in \u03b11\u03b23\u03b32-, \u03b12\u03b23\u03b32-, \u03b13\u03b23\u03b32-, and \u03b15\u03b23\u03b32-containing GABAA receptors to determine the ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparable binding affinities, while for the other two chemotypes, a discrepancy in binding affinities of the different isomers was observed. Specifically, the R isomers displayed a loss of binding, whereas the S isomers remained active. These findings are in accordance with the results of our in silico studies suggesting the usage of a different binding mode of imidazobenzodiazepines compared to those of the other two tested chemotypes. Hence, we conclude that different chemically related benzodiazepine ligands interact via distinct binding modes rather than by using a common binding mode.<\/jats:p>","DOI":"10.1021\/acschembio.8b00144","type":"journal-article","created":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T13:59:00Z","timestamp":1526479140000},"page":"2033-2039","source":"Crossref","is-referenced-by-count":38,"title":["Different Benzodiazepines Bind with Distinct Binding\nModes to GABAA Receptors"],"prefix":"10.1021","volume":"13","author":[{"given":"Alshaimaa A.","family":"Elgarf","sequence":"first","affiliation":[{"name":"Medical University of Vienna , , ,","place":["Vienna, Austria, 1090"]},{"name":"Ain Shams University , , ,","place":["Cairo, Egypt"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7132-9765","authenticated-orcid":true,"given":"David C. B.","family":"Siebert","sequence":"additional","affiliation":[{"name":"TU Wien , , ,","place":["Vienna, Austria, 1060"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Steudle","sequence":"additional","affiliation":[{"name":"Medical University of Vienna , , ,","place":["Vienna, Austria, 1090"]},{"name":"Medical University of Vienna , , ,","place":["Vienna, Austria, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelika","family":"Draxler","sequence":"additional","affiliation":[{"name":"Medical University of Vienna , , ,","place":["Vienna, Austria, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanguan","family":"Li","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Milwaukee , , , ,","place":["Milwaukee, Wisconsin, United States, 53211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengming","family":"Huang","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Milwaukee , , , ,","place":["Milwaukee, Wisconsin, United States, 53211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-3022","authenticated-orcid":true,"given":"James M.","family":"Cook","sequence":"additional","affiliation":[{"name":"University of Wisconsin\u2500Milwaukee , , , ,","place":["Milwaukee, Wisconsin, United States, 53211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Ernst","sequence":"additional","affiliation":[{"name":"Medical University of Vienna , , ,","place":["Vienna, Austria, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-6034","authenticated-orcid":true,"given":"Petra","family":"Scholze","sequence":"additional","affiliation":[{"name":"Medical University of Vienna , , ,","place":["Vienna, Austria, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,5,16]]},"reference":[{"key":"2026090213581812900_cit1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1001\/jamapsychiatry.2014.1763","article-title":"Benzodiazepine use in the United\nStates","volume":"72","author":"Olfson","year":"2015","journal-title":"JAMA Psychiatry"},{"key":"2026090213581812900_cit2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0031-6997(25)06840-1","article-title":"Structure\nand pharmacology of GABAA receptor subtypes","volume":"47","author":"Sieghart","year":"1995","journal-title":"Pharmacol. Rev."},{"key":"2026090213581812900_cit3","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/bs.apha.2014.10.002","article-title":"Allosteric\nModulation of GABAA Receptors via Multiple Drug-Binding\nSites","volume":"72","author":"Sieghart","year":"2015","journal-title":"Adv. Pharmacol."},{"key":"2026090213581812900_cit4","doi-asserted-by":"publisher","first-page":"217","DOI":"10.2174\/1568015054863837","article-title":"Heterogeneity of GABAA Receptors: Revived Interest in\nthe Development of Subtype-selective Drugs","volume":"5","author":"Sieghart","year":"2005","journal-title":"Curr. Med. Chem.: Cent. Nerv. Syst. Agents"},{"key":"2026090213581812900_cit5","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1146\/annurev-pharmtox-011613-135947","article-title":"GABAA receptor\nsubtypes: Therapeutic potential\nin Down syndrome, affective disorders, schizophrenia, and autism","volume":"54","author":"Rudolph","year":"2014","journal-title":"Annu. Rev. Pharmacol. 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Pharmacol."},{"key":"2026090213581812900_cit28","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","article-title":"Comparative protein\nmodelling by satisfaction of spatial\nrestraints","volume":"234","author":"Sali","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2026090213581812900_cit29","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3389\/fnmol.2016.00044","article-title":"Structural\nStudies\nof GABAA Receptor Binding Sites: Which Experimental Structure\nTells us What?","volume":"9","author":"Puthenkalam","year":"2016","journal-title":"Front. Mol. Neurosci."},{"key":"2026090213581812900_cit30","unstructured":"Huang, S.\n           (2007) Synthesis of Optically Active Subtype\nSelective Benzodiazepine Receptor\nLigands. Ph.D. Thesis, University\nof Wisconsin\u2500Milwaukee, Milwaukee,\nWI."}],"container-title":["ACS Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acschembio.8b00144","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/13\/8\/2033\/66949267\/acschembio.8b00144.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/13\/8\/2033\/66949267\/acschembio.8b00144.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:58:27Z","timestamp":1788371907000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acbcct\/article\/13\/8\/2033\/830820\/Different-Benzodiazepines-Bind-with-Distinct"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,16]]},"references-count":30,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2018,5,16]]},"published-print":{"date-parts":[[2018,8,17]]}},"URL":"https:\/\/doi.org\/10.1021\/acschembio.8b00144","relation":{},"ISSN":["1554-8929","1554-8937"],"issn-type":[{"value":"1554-8929","type":"print"},{"value":"1554-8937","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,16]]}}}